Methods for selecting protease resistant polypeptides
a protease resistant polypeptide and polypeptide technology, applied in the field of protease resistant polypeptide selection, can solve the problems of in vitro use potential of agents, many therapeutic peptides, polypeptides and proteins, etc., and achieve enhanced stability, improved or relatively high melting temperatures (tm), and high affinity target binding
Active Publication Date: 2014-04-01
GLAXO GRP LTD
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Benefits of technology
The method produces peptides that remain active and functional for longer, maintaining biological activity and stability, even in protease-rich environments, enhancing their therapeutic potential for conditions like diabetes and inflammatory diseases.
Problems solved by technology
However, many therapeutic peptides, polypeptides and proteins are particularly susceptible to degradation in vivo by naturally occurring proteases.
Accordingly, some agents that have potential for in vivo use (e.g., use in treating, diagnosing or preventing disease in mammals such as humans) have only limited efficacy because they are rapidly degraded and inactivated by proteases.
Furthermore, via its ability to enhance satiety, GLP-1 reduces food intake, thereby limiting weight gain, and may even cause weight loss.
However, its pharmacokinetic / pharmacodynamic profile is such that native GLP-1 is not therapeutically useful.
Thus, while GLP-1 is most effective when administered continuously, single subcutaneous injections have short-lasting effects.
However, despite these efforts a long lasting active GLP-1 has not been produced.
Method used
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example 1
Aim of the Study
[0226]The aim of the study was to obtain protease resistant variants of GLP-1 ALBUDAB™ fusions by performing phage selection on a libraries derived from a GLP-1 variant comprising DPP IV resistant GLP-1 (referred to as herein as *GLP-1) in combination with treatment of phage with various proteases (including those naturally occurring in the expression host). As described herein, an ALBUDAB™ is an immunoglobulin single variable domain that specifically binds serum albumin.
GLP-1 Receptor
[0227]The glucagon-like peptide-1 receptor (GLP-1R) belongs to the family B1 of seven transmembrane G protein-coupled receptors. Binding interactions between the receptor and its natural agonist ligand GLP-1 is initiated by ligand binding to extracellular N-terminal domain of the receptor (ECD GLP-1R) and followed by interaction with the core of transmembrane portion (Al-Sabah et al, 2003; FEBS Lett; 553(3): 342-6). It has been shown that GLP-1 binding to the isolated N-terminal domain ...
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Abstract
The disclosure relates to a method for selecting, isolating and / or recovering a peptide or polypeptide from a library or a repertoire of peptides and polypeptides (e.g., a display system) that is resistant to degradation by a protease such as a protease found in the serum. Generally, the method comprises providing a library or repertoire of peptides or polypeptides, incubating the library or repertoire with a protease under conditions suitable for protease activity, and selecting, isolating and / or recovering a peptide or polypeptide that is resistant to degradation by the protease and has a desired biological activity. The selected peptides and polypeptides have utility as therapeutics, e.g., for treating disease in humans.
Description
[0001]This application is a 371 of International Application No. PCT / EP2009 / 066395, filed Dec. 4, 2009, which claims the benefit of U.S. Provisional Application No. 61 / 120,135, filed Dec. 5, 2008, which is incorporated herein in its entirety.BACKGROUND OF THE DISCLOSURE[0002]Polypeptides and peptides have become increasingly important agents in a variety of applications, including industrial applications and use as medical, therapeutic and diagnostic agents. However, many therapeutic peptides, polypeptides and proteins are particularly susceptible to degradation in vivo by naturally occurring proteases. Moreover, in certain physiological states, such as inflammatory states (e.g., COPD) and cancer, the amount of proteases present in a tissue, organ or animal (e.g., in the lung, in or adjacent to a tumor) can increase. This increase in proteases can result in accelerated degradation and inactivation of endogenous proteins and of therapeutic peptides, polypeptides and proteins that are...
Claims
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IPC IPC(8): C40B40/10
CPCC12Q1/37G01N33/6845G01N2500/02G01N33/6857A61P3/10C40B40/10C12N5/06
InventorENEVER, CAROLYNJESPERS, LAURENTPUPECKA, MALGORZATATOMLINSON, IAN M
OwnerGLAXO GRP LTD